Butylsulfamylbenzoic acid



Patented Aug. 26, 1952 Sharp & Dohme, Incorporated,Philadelphia, Pa.,acorporation of Maryland No Drawing. Application June 28, 1950,

Serial No. 170,938

. This invention relates to anew compound which is effective as an adjuvant for use in conjunctionwith the administration of, penicillin to provide an increasein the blood plasma penicillin concentration with a given dose of penicillin, thereby making possible very high penicillin blood levels, or permitting the use of smaller quantities of penicillin for providing a given blood level, or permitting the less frequent administration of penicillin while maintaining a penicillin blood level adequate forrbactericidal or bacteriostatic purposes. .The invention also relates to the preparation of various dosage .forms in which this new compound is incorporated for administration by various routes.

Penicillin appears to be almost quantitatively excreted from the blood by theepithelial cells of the tubules, at least within plasma concentrations which have been explored, with the result that itsrate of excretion from the blood stream isqapproximately five times that of materials which areexcreted by glomerular filtration alone, the tubular excretion accounting for about 80- 8 l) and the glomeruli about 20 (19) {Various proposals have been made to overcome the difliculties due to the rapid elimination of penicillin, such as the administration of it in suspension in an oleaginous material, the mixture being administered by intramuscular injection.

A second proposal which has been made has been to use a material such as diodrast or para-aminohippuric acid which, like penicillin, is selectively excreted by the tubules. Neither of these proposals has afforded a satisfactory solution to the problem, since the use of an oleaginous suspension of penicillin merely prolongs the time interval between injections and does not provide a high blood level of penicillin and, while the second proposal provides a means to, inhibitthe excretion of penicillin by the kidney tubules to a substantial extent, it does so at the expense of overloading the tubules with materials which they function to remove from the blood.

2 Claims. (01. 167-55) dium with a weak, alkaline substance, such as an aqueous sodium bicarbonate solution, filter- The present invention is based upon the discovery that removal of penicillin from the blood stream by the kidney tubules can be efiectively blocked by the new adjuvant of this invention,

para-(iso-butylsulfamyl) benzoic acid, having the general formula C H\a V a ICHC2 1 ,N- QG QHY H, 1 e and its salts. l v 3 The new suliamyl benzoicac'id of" the invention is generally made byfirst preparing a paracarboxybenzenesulfonyl"halide by oxidation of para-toluenesulfonyl i halide, or by fpreparing -para-cyanobenzenesulfonyl halide by treating para-sulfamyl benzoic acid with phosphorus pentachloridei halide or para-cyanobenzenesulfonylhalide thus The para carboxybenzenesulfonyl formed is reacted withthe iso-butylamina'advantageously usingan excessgfor example. two to three equivalents, of the amine, and when the cyanobenzenesulionyl halide reactant is used, hydrolyzing the product thus formed to the corresponding carboxyl derivative. The reaction is preferably carried-out inthe presence of a solvent, such as" acetone or-pyridine and thelike, or in aqueous sodium hydroxide, and preferably with cooling. Any by-productformed duringthe reaction is removed by treating the reaction meing ofi the precipitated by-product, and then recovering the para-(iso-butylsulfamyl)-benzoic acid from the filtrate by acidification.

The preparation'of the new compound of the invention is illustrated by, but not restricted to the following example:

Para-(isobutylsulfamylybenzoic acid.To 21.93 grams (0.3 mol) of iso-butylamine dissolved in. 200cc. of acetone, contained in an open flask provided with a stirrer,22.05grams' (0.1 mol) of p-carboxybenzenesulfonyl chloride was added'in portions with cooling and stirring. The reaction was stirred for one-half hour after which the mixturewas placed one; steam bath to evaporate the acetone. The residue was diluted with water 'until the...volume was increasedto about 600 cc., and then made acid with dilute hydrochloric acid. The crude product precipitated, was removed 'by filtration, and washed. 4 The wet solid material was redissolved in dilute sodium bicarbonate solu- -about to mg. per'100 00.,

tion, the insoluble material separated by filtration and the filtrate treated with decolorizing charcoal. The charcoal was filtered on and the filtrate made acid with dilute hydrochloric acid precipitating 16.9 grams of the product which, after recrystallization from alcohol, melted at 234-235 C.

The para-(iso-butylsulfamyl)-benzoic acid of this invention is relatively non-toxic, it is soluble in blood plasma and operates, when carried by the blood stream into contact with the tubules, to prevent their normal action in removing penicillin from the blood stream. The ad juvant itself is notexc'reted to any substantial extent by the tubules, and the available evidence indicates that on coming into contact with the epithelial cells of the tubules, it operates to block their action by interference with the normal functioning of the epithelial cells and does not inhibit the excretion of the penicillin by competing with it within the tubular functional capacity. Thus, the adjuvant is effective in eliminating or very radically reducing tubular excretion of penicillin in plasma concentrations around 10 mg. per 100 cc., which'is about the threshold value for agents such as p-aminohippuric acid or diodrast. The highly effective adjuvant of this invention will reduce; the excretion of penicillin by the tubules, at a blood plasma concentration of about 10 mg. per 100 cc.

Compressed tablets Part I .4,548 grams of corn starch are hydrolyzed with- 40 liters of hot water. 50,000 grams of para-(iso-butylsuliamyl) -benzoic acid are added to the wet paste and the entire mass is then granulated. The wet granulated material is passed through a coarse screen, spread thinly on trays and dried in an oven at about 60 C. for

24 hours and then passed through a, N0. 14 screen.

Part II.131 grams of ethyl cellulose (having a low viscosity, e. g., centipoise) are dissolved in 3.5 liters of anhydrousalcohol with the aid of to almost zero, so that the actual elimination of penicillin from the blood stream becomes substantially that resulting from glomerularfiltration, that is, aboutpone-fi fth the normal rate (ignoring plasma binding). The adjuvant itself .is eliminated by the glomeruli.

The .adjuvant can be administered orally. or, when dissolved in an aqueous solution, it can be administered intravenously or intramuscularly, and in either case, in admixture with penicillin or separately: therefrom.

Whether the adjuvant is administered in admixture with or separately from the penicillin, the quantity used should be such as to provide a concentration in the blood stream of adjuvant adequate to block substantially the excretory mechanism of the tubules Maximum effect will be obtained with blood plasma concentrations of obtainable at dosage levels of about 4 to 16 grams per day orally and somewhat less than this intravenously. In a composition comprising both penicillin and the adjuvant, a ratio of about 0.5 gram of adjuvant to from 25,000to 200,000 units of penicillin is advantageous.

In general, oral administration of the adjuvant at the-rate of 4 to 16 grams per day is adequate to suppress the rate of penicillin'excretion to an extent such that the blood level with a iven dose of penicillin administered orally or intramuscularly in aqueous solution will be in creased to as much as four times the level ob- ,tainedwithout the use of the adjuvant.

' The adjuvant may be prepared many convenient dosage form, either alone or admixed with penicillin, such as in a compressed tablet, a dry yfilled capsule or a soft elastic capsule. It is to-be understood, of course, that'otheringredientssuch as binders, diluents, excipients, 'ant- :acid substancesor other inert or therapeutically active compounds mayibe. incorporatedinto any .selected dosage -'form along with the. adjuvant or adjuvant plus'penicillin, provided the added ingredient does not destroy the activity of either the adjuvant or penicillin. Similarly, the adgentle heating and in an atmosphere controlled at 30% relative humidity at 25 C. In a separate container, 6,666 grams of penicillin G sodium, 5,425 grams of powdered sodiumbicarbonate and 1,618 grams of dried corn starch are intimately mixed. together. and then passed through a fine screen. This mixed powder granulated with the Warm solution of ethyl cellulose, adding additional anhydrous alcohol, if necessary, to form good granules. The granulated material is passed through a coarse screen, spread on trays and dried in an oven at 55 C. for 14 hours and then passed through a No. 20 screen.

The granules obtained in part I and part II are combined and mixed with4,927 grams of granular sodium bicarbonate and then 6,660 grams of dried corn starch are intimately mixed therein.

After thorough stirring, 7,000 grams of dried talc and 525 grams of magnesium stearate are added and the mixture again thoroughly stirred. This final mixture is compressed into tablets using a one-half inch die and flat face, double edge punches yielding 100,000 tablets each Weighing 0.875 gram and containing 0.5 gram of para-(isobutylsulfamyl) -benzoic acid and l00,000-units (plus-10% excess) of penicillin G sodium."

Incompositions containing penicillin, it is advisable, in accordance with customarypractice, to include an excess of the penicillin, for example, a ten per cent excess over the labelclaimed quantity in accordance with present practice. An excess of penicillin introduces no difficulty save its cost. The penicillin usedmay be any of the forms available for'use, such as the calcium, sodium, potassium, procaine; and the like-salts of amorphous or crystalline penicillin. Y Having now particularly describedthe invention, what is claimed is:-

f1. adjuvant which is a member of the group consisting of para-(iso-b1itylsulfamyl)-benzoic acid having the formula v our N-soe oo0-H v H V f and its non-toxic, water-soluble salts. 2, A composition suitable for therapeutic use, comprising penicillin and an iadjluvant .whichilis a member of the group consisting of para-(isobutylsulfamyl) -benzoic acid having the formula REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Andersen June 13, 1939 OTHER. REFERENCES Reid, Prolongation of Penicillin Activity with Penicillinase-Inhibiting Compounds, Proc. Soc. Exptl. Biol. and Med, Nov. 1946, pages 438-443.

Soc-H00, Activity of Penicillin Combined with Number 10 Other Anti-Streptococcal Agents Archives Biochemistry, Sept. 1944, pages 99-106.

Meade, Caronamide and. Penicillin, J. Am. Med. Assoc, Nov. 20, 1948, pages 874-877.

Pratt, et a1, Antibiotics, Lippincott 00., 1949,

15 pp. 112-116. (BOOk in Division 43.) 

2. A COMPOSITION SUITABLE FOR THERAPEUTIC USE, COMPRISING PENICILLIN AND AN ADJUVANT WHICH IS A MEMBER OF THE GROUP CONSISTING OF PARA-(ISOBUTYLSULFAMYL)-BENZOIC ACID HAVING THE FORMULA 